Prostaglandin E2 (PGE2) has been known as a metabolite in the arachidonic acid cascade. It has been known that PGE2 possesses cyto-protective activity, uterine contractile activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awaking effect, a suppressive effect on gastric acid secretion, hypotensive activity, and diuretic activity.
In the recent study, it was found that PGE2 receptor was divided into some subtypes, which possesses different physical roles from each other. At present, four receptor subtypes are known and they are called EP1, EP2, EP3 and EP4 respectively [Negishi M. et al, J. Lipid Mediators Cell Signaling 12, 379-391 (1995)].
PGE2 has a broad range of a physiologically active, therefore it has a fault that an activity other than a purpose will become a side effect. However, it has been studied to overcome the fault by a reserch of each subtype role and a synthesis of compounds having an effective action for one subtype only.
Among these subtypes, it is known that EP1 subtype relates to pain, fever, diuresis [Br. J. Pharmacol., 112, 735-40 (1994); European J. Pharmacol., 152, 273-279 (1988); Gen Pharmacol., September 1992, 23(5), 805-809]. Therefor, it is believed that an antagonism for this receptor is useful as analgesics, antipyretic or a therapeutic agent of frequent urination.
Besides, it is known that EP1 antagonists have an inhibitory activity of a formation of abnormal crypt in the lining of the large intestine and polyp in the intestine, and show an anticancer activity [see reference WO 00/69465].
Depression is led by various factors, and the pathological physiology is remained incompletely understood. Monoamine reuptake inhibitor and monoamine oxidase (MAO) inhibitor are showed an antidepressive activity, and it is consider that an abnormal mono-aminergic neuron system plays a role in the development of depression.
As an antidepressant, MAO inhibitors including hydrazine derivatives, emotion stimulators such as a reuptake inhibitor of noradrenaline (NA) and 5-hydroxytryptamine (5-HT), emotion regulators including benzodiazepine derivatives and psychostimulants including Meratoran are known. Then, MAO inhibitors are not used because of a serious hepatopathy and hypertensive crisis, and new type reuptake inhibitor of NA and 5-HT are used, that they are improved side effects such as dry mouth, drowsiness, dizziness, urinary disturbance that are side effects of tricyclic antidepressants as typified by imipramine.
On the other hand, it was not confirmed by an experiment that a relationship of EP1 receptors and depression and antidepressive activity of EP1 antagonist.